Discovery of Quinoline‐Derived Trifluoromethyl Alcohols,Determination of Their in vivo Toxicity and Anticancer Activity in a Zebrafish Embryo Model

In this study the rational design, synthesis, and anticancer activity of quinoline‐derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp³‐C?H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4‐trifluoro‐3‐hydroxy‐3‐(quinolin‐2‐ylmethyl)butanoate ( 1 ), 2‐benzyl‐1,1,1‐trifluoro‐3‐(quinolin‐2‐yl)propan‐2‐ol ( 2 ), and trifluoro‐3‐(isoquinolin‐1‐yl)‐2‐(thiophen‐2‐yl)propan‐2‐ol ( 3 ). Compounds 2 and 3 were found to be more toxic than compound 1 ; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2 , with an LC₅₀ value of 14.14 μm , has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents.     

Serum Amyloid A Receptor Blockade and Incorporation into High-Density Lipoprotein Modulates Its Pro-Inflammatory and Pro-Thrombotic Activities on Vascular Endothelial Cells

The acute phase protein serum amyloid A (SAA), a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF) in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC). HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1), WRW4; receptor for advanced glycation-endproducts (RAGE), (endogenous secretory RAGE; esRAGE) and toll-like receptors-2/4 (TLR2/4) (OxPapC), before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL), a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.     

In Situ Reacted Rare-Earth Hexaaluminate Interphases

A novel in situ reaction between a ceria-doped zirconia interphase coating on Saphikon fibers and an outer alumina coating has resulted in the formation of oriented hexaaluminate platelets which can act as a low fracture energy interface barrier for crack deflection in oxide-oxide ceramic-matrix composites (CMCs). The reaction proceeds only in reducing environments where the reduction of the cerium and zirconium ions to their 3+ valent state causes a destabilization phenomenon consistent with previously reported findings. The diffusion of the cerium from the zirconia into solid solution with the alumina can stabilize the layered hexaaluminate structure. Preferred orientational growth of the hexaaluminate parallel to the coating interface was observed which is the required orientation for enhanced debonding at the fiber/matrix interface in long-fiber-reinforced CMCs.     

The averaged periodogram estimator for a power law in coherency

We prove the consistency of the averaged periodogram estimator (APE) in two new cases. First, we prove that the APE is consistent for negative memory parameters, after suitable tapering. Second, we prove that the APE is consistent for a power law in the cross‐spectrum and therefore for a power law in the coherency, provided that sufficiently many frequencies are used in estimation. Simulation evidence suggests that the lower bound on the number of frequencies is a necessary condition for consistency. For a Taylor series approximation to the estimator of the power law in the cross‐spectrum, we consider the rate of convergence and obtain a central limit theorem under suitable regularity conditions.     

Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2

Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.     

Processing and electromechanical properties of high-coercive field ZnO-doped PIN-PZN-PT ceramics

This study explores sintering and piezoelectricity of ZnO-doped perovskite Pb(In_1/2Nb_1/2)O₃-Pb(Zn_1/3Nb_2/3)O₃-PbTiO₃ (PIN-PZN-PT) ceramics. The enhanced densification of ZnO-doped PIN-PZN-PT is attributed to the formation of oxygen vacancies by the incorporation of Zn²⁺ into the perovskite B-site and increased rate of bulk diffusion relative to undoped PIN-PZN-PT. Incorporation of Zn²⁺ into the perovskite lattice increased the tetragonal character of PIN-PZN-PT as demonstrated by tetragonal peak splitting and increased Curie temperature. Sintering in flowing oxygen reduced the solubility of Zn²⁺ in the perovskite lattice and resulted in rhombohedral PIN-PZN-PT. Sintering in oxygen prevented secondary phase formation which resulted in a high-piezoelectric coefficient (d₃₃ – 550 pC/N), high-coercive field (E_c – 13 kV/cm), and high-rhombohedral to tetragonal phase transition temperature (T_r-t – 165°C). We conclude that ZnO-doped PIN-PZN-PT ceramics are excellent candidates for high-power transducer applications.     

EGFR-Binding Peptides: From Computational Design towards Tumor-Targeting of Adeno-Associated Virus Capsids

The epidermal growth factor receptor (EGFR) plays a central role in the progression of many solid tumors. We used this validated target to analyze the de novo design of EGFR-binding peptides and their application for the delivery of complex payloads via rational design of a viral vector. Peptides were computationally designed to interact with the EGFR dimerization interface. Two new peptides and a reference (EDA peptide) were chemically synthesized, and their binding ability characterized. Presentation of these peptides in each of the 60 capsid proteins of recombinant adeno-associated viruses (rAAV) via a genetic based loop insertion enabled targeting of EGFR overexpressing tumor cell lines. Furthermore, tissue distribution and tumor xenograft specificity were analyzed with systemic injection in chicken egg chorioallantoic membrane (CAM) assays. Complex correlations between the targeting of the synthetic peptides and the viral vectors to cells and in ovo were observed. Overall, these data demonstrate the potential of computational design in combination with rational capsid modification for viral vector targeting opening new avenues for viral vector delivery and specifically suicide gene therapy.     

Anti-biofilm Activity of Human Milk Oligosaccharides in Clinical Strains of Streptococcus agalactiae with Diverse Capsular and Sequence Types

Group B Streptococcus (GBS) is an encapsulated Gram-positive bacterial pathogen that causes severe perinatal infections. Human milk oligosaccharides (HMOs) are short-chain sugars that have recently been shown to possess antimicrobial and anti-biofilm activity against a variety of bacterial pathogens, including GBS. We have expanded these studies to demonstrate that HMOs can inhibit and dismantle biofilm in both invasive and colonizing strains of GBS. A cohort of 30 diverse strains of GBS were analyzed for susceptibility to HMO-dependent biofilm inhibition or destruction. HMOs were significantly effective at inhibiting biofilm in capsular-type- and sequence-type-specific fashion, with significant efficacy in CpsIb, CpsII, CpsIII, CpsV, and CpsVI strains as well as ST-1, ST-12, ST-19, and ST-23 strains. Interestingly, CpsIa as well as ST-7 and ST-17 were not susceptible to the anti-biofilm activity of HMOs, underscoring the strain-specific effects of these important antimicrobial molecules against the perinatal pathogen Streptococcus agalactiae.     

Study of stability of high‐temperature polyimides using TG/MS technique

The oxidative stability of the carbon fiber‐reinforced composite of polyimide was examined, in real time, using the evolved gas analysis techniques. Off‐gas degradation products suggested the onset temperature for chain scissions to be fairly low at about 190–220°C. Based on the off‐gas products present and the trend of their release, the composite degradation mechanism appeared to be similar between 190 and 371°C, thereby marking 371°C to be the highest accelerated aging temperature for its long‐term lifetime prediction. Beyond 371°C, different degradation mechanisms would apply. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 1219–1227, 2002